PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and the third most common cause of cancer death worldwide; while incidence and mortality rates are two times higher in Latinos, incidence rates are the highest among Latinos in the South Texas region. The genetic events associated with the increased incidence of HCC in this population are largely unknown. Identification of unique genetic markers, in combination with implementation of known risk factors in South Texas Latinos (i.e. obesity and fatty liver disease), could be instrumental for understanding the mechanisms driving the increased incidence, and for development of new treatment modalities. We performed whole genome RNA sequencing in paired HCC tumor and adjacent normal tissue total RNA from nine South Texas Latino patients. Analysis of differentially expressed genes revealed significant alterations in pathways associated with oxidative stress and mineral uptake; most importantly, we found that the expression of STEAP2 (Six Transmembrane Epithelial Antigen of the Prostate 2) is increased five-fold in HCC tumor tissue compared to adjacent-normal tissue. In comparison to a non-Latino population, this finding was unique to South Texas Latinos. STEAP2 is a metalloreductase of iron and copper, the reduction process facilitates transfer of iron and copper into cells. Reduced iron and copper ions can mediate the production of hydroxyl radicals resulting in increased oxidative stress, which can cause DNA damage and lipid peroxidation. Interestingly, we found significantly higher levels of total copper and markers of oxidative stress in HCC tissue compared to adjacent normal liver tissue. In our studies, knockdown of STEAP2 expression in human HCC cell lines significantly inhibited cell viability, motility, and clonogenicity in soft agar, suggesting a malignant-promoting role in HCC. Given these findings, an immediate need exists to find the mechanistic links between STEAP2, iron and copper levels, oxidative stress and HCC development and progression. Therefore, we hypothesize that STEAP2 will lead to an increase in oxidative stress, lipid peroxidation, and cell growth in the hepatocytes resulting in enhanced tumorigenesis and tumor progression in HCC, especially in obese hosts. Two specific aims are proposed to test our hypothesis. Aim 1. Determine the mechanisms by which STEAP2 acts as an oncogenic factor and a contributor to increased oxidative stress, lipid peroxidation and labile iron and copper levels. Aim 2. Establish the effect of liver-specific STEAP2 overexpression on increased liver steatosis and tumorigenesis in combination with a high fat diet. The gene to be studied is a unique metalloreductase that may modulate the crosstalk between iron/copper levels, obesity, oxidative stress and HCC carcinogenesis. Verification of our hypothesis would indicate a possible role of STEAP2 as a novel therapeutic target for HCC in the Latino population and other cancer types as well. Our animal studies will reveal in vivo function of STEAP2 in combination with a high fat diet, and provide better mouse HCC models for studying HCC tumorigenesis and drug screening.